Serotonin or 5-hydroxytryptamine (5-HT) is a major neurotransmitter that is primarily found in the gastrointestinal tract, platelets, and the central nervous system (CNS). 5-HT is involved in the regulation of a variety of physiological functions, such as intestinal movements, mood, cognition, and appetite (1). These functions are mediated through serotonin receptors, which belong to the G-protein coupled receptor (GPCR) superfamily and are composed of seven subfamilies (5-HT1-7) and 14 isoforms (2).
Recently, the serotonin 2C (5-HT2C) receptor has been shown to be a promising drug target for the treatment of a variety of CNS disorders, including obesity and mental disorders, such as schizophrenia, depression, and anxiety (3). Furthermore, based on the study of both its distribution and biological function, 5-HT(2C) receptors in the basal ganglia likely are essential for the regulation of repetitive motion and in the cingulate gyrus they mediate many of the effects of neurotransmitters on obsessive/compulsive-type behaviors. Therefore, 5-HT(2C) receptor agonists can be useful for the treatment of some neurological disorders, such as Rett syndrome.
One of the many advantages of the 5-HT2C receptor as a CNS drug target stems from the fact that it is found almost exclusively in the CNS (4). Therefore, compounds that selectively activate this receptor should have limited impact on peripheral tissues. However, the activation of two other closely related 5-HT2 subtypes, i.e., 5-HT2A and 5-HT2B receptors, has been reported to be associated with hallucinations and cardiac valvulopathy, respectively (5). Therefore, the identification of ligands possessing a high selectivity against the 5-HT2A and 5-HT2B receptors is a key criterion for the therapeutic advancement of 5-HT2C agonists. This goal has been challenging due to the high conservation of molecular determinants involved in ligand recognition within this subfamily of receptors (6).
Currently, a number of 5-HT2C agonists (Table 1) having potential therapeutic uses or as a chemical tool for the study of the biological roles of 5-HT2C receptor are being evaluated. Among them, lorcaserin (Belviq) was approved for the treatment of obesity. Although it was reported to have 100-fold selectivity for 5-HT2C relative to the 5-HT2B subtype, lorcaserin possesses full agonist activity at 5-HT2B (EC50=943±90 nM, Emax=100%) (7). Hence, it is not surprising that lorcaserin was found to cause a higher incidence of cardiac valve disorders in clinical trials compared to the placebo group (8). Vabicaserin (SCA-136) targets 5-HT2C receptors (EC50=8 nM, Emax=100%) and was tested in clinical trials for the treatment of schizophrenia (9). However, it displayed moderate efficacy on 5-HT2B receptors (Emax=50%) and good potency (EC50=12 or 102 nM depending on receptor densities) (10). WAY-163909, an analogue of vabicaserin, was shown to have selectivity toward 5-HT2C (EC50=8 nM; Emax=90%), while possessing no agonist activity at 5-HT2A and weak efficacy at 5-HT2B receptors (Emax=40%). WAY-163909 has a good preclinical antipsychotic-like activity in several animal models (11). Compound CP-809,101 is one of the most selective and potent 5-HT2C (EC50=0.11 nM, Emax=93%) ligands developed, with about 600-fold 5-HT2C selectivity against 5-HT2B. However, it is still relatively potent at 5-HT2B (EC50=65.3 nM, Emax=57%) (12). Due to the genotoxicity of this compound, it could not be advanced to clinical evaluation (13). Nonetheless, CP-809,101 has structural similarities to mCPP and MK-212, two compounds discovered decades ago and used as tools for the pharmacological study of 5-HT2C receptors (14).
TABLE 1Representative 5-HT2C agonists.     
Compounds that possess the 2-phenylcyclopropylmethylamine scaffold were developed as selective 5-HT2C agonists. This particular scaffold was derived from an initial high throughput screening (HTS) screening campaign in which tranylcypromine was identified as a hit (15). Research led to the identification of compounds possessing a 2-cyclopropylmethoxy group at position 2, as illustrated by the compounds in Table 2. The compound, possessing a fluorine substitution at position 5 of the benzene ring, showed good potency on the 5-HT2C receptor (EC50=21 nM), with only moderate selectivity for 5-HT2B(EC50=289 nM) (16). Replacement of the fluorine atom with a hydroxyl group led to the enhancement of both potency and selectivity, but the bioavailability was found to be too low (F=3.2% in mice, unpublished data). A compound lacking substitution at the same position showed good potency as a partial agonist (EC50=55 nM, Emax=61%), with excellent selectivity against both 5-HT2A and 5-HT2B (17).
TABLE 2Selective 5-HT2C agonists based on 2-phenylcyclopropylmethylamino scaffold.
These findings indicate that a need exists in the art for drugs that interact selectively with 5-HT(2) receptor subtypes, and, in particular, selective 5-HT(2C) receptor agonists, which exhibit minimal effect on 5-HT(2A) and 5-HT(2B) receptors. Selective 5-HT(2C) receptor agonists can be useful for treatment obesity and related or associated disorders, including hypertension, hyperlipidemia, diabetes, and cardiovascular disease, and avoid interaction with several related and unrelated receptors associated with significant morbidity and mortality, e.g., valvular heart disease associated with activation of the 5-HT(2B) receptor subtype and hallucinations associated with activation of the 5-HT(2A) receptor subtype.
Selective 5-HT(2C) receptor agonists can be useful in the treatment of depression, anxiety, panic disorder, schizophrenia, OCD, epilepsy, migraine and Rett syndrome. In addition, 5-HT(2C) receptor agonists are further disclosed in WO 2006/065600 and WO 2007/025144 as useful for treatment of Alzheimer's Disease, in prevention or treatment of senile plaques, and in the treatment of sexual dysfunction in males and females, including the treatment of erectile dysfunction.
A number of synthetic compounds have been reported that show 5-HT(2C) receptor agonistic activity, including in U.S. Pat. Nos. 6,962,939; 6,777,407; 7,012,089; 6,953,787; and 7,071,185; U.S. Patent Publication Nos. 2005/197380; 2005/020573; 2006/154290; 2005/026925; 2005/0143452; 2002/032199; and 2005/0261347; and published PCT applications WO 2000/035922; WO 2006/065600; WO 2006/077025; and WO 2005/007614, for example.
An important advance in the art would be the discovery of selective 5-HT(2C) receptor agonists that are useful in the treatment of diseases and conditions wherein 5-HT(2C) receptor agonism provides a benefit, such as psychiatric disorders, addictive behaviors, cognition disorders, obesity, movement disorders, and compound addiction, for example. A significant need exists in the art for efficacious compounds, compositions, and methods useful in the treatment of such diseases and conditions, alone or in conjunction with other therapies used to treat these diseases and conditions. The present invention is directed to meeting this need.